Rodríguez‐Porcel, Federico

Abstract Background Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors. Objective The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population‐based cohort. Methods We performed a matched nested case–control study using the UK Biobank (UKB) cohort consisting of >500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach. Results There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30–4.50; P < 0.001), delirium (OR, 6.76; 95% CI, 4.08–11.19; P < 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39–2.63; P < 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21–2.26; P = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40–0.79; P < 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis. Conclusions In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.

Background Motor speech disorders are early, common, and functionally limiting features of atypical parkinsonian disorders (APDs) such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA). These impairments are underrecognized and undertreated in neurology clinics. Objectives This review aims to characterize speech impairment in APDs, offer practical guidance for clinical evaluation, highlight the role of Speech‐Language pathologists (SLPs) in diagnosis and management, and outline current and emerging management strategies. Methods A narrative review was conducted by the Diagnosis and Treatment Working Group of CurePSP's Centers of Care, integrating literature and clinical experience to summarize evaluation, diagnosis, and treatment of motor speech disorders in APDs. Results Speech changes in APDs are often mixed dysarthrias with hypokinetic, spastic, and/or ataxic components, and may include apraxia of speech; these are frequently more severe and progress quicker than in Parkinson's disease. These features can assist in differential diagnosis and should prompt early referral to SLPs. Despite the high prevalence of speech and voice changes, comprehensive assessment of motor speech disorders is uncommon in neurology clinics. Current evidence regarding the efficacy of interventions is mixed. Digital acoustic analysis and neuromodulation offer promising directions for diagnosis and treatment. Conclusions Early, collaborative management of motor speech impairment elevates care in APDs. Neurologists and SLPs must work together to improve recognition, diagnosis, and care. Future research should focus on objective biomarkers and personalized therapies to support communication, autonomy, and quality of life for individuals living with APDs.

Abstract Background Trials in Lewy body dementia (LBD) rely on scales and measurements created for Alzheimer’s disease and Parkinson’s disease. Industry and regulatory authority stakeholders and LBD triallists have recognised the absence of an LBD‐specific scale as critical unmet need in the drug development pipeline. Heterogeneity in LBD trials design, particularly concerning outcome measures, precludes effective evidence synthesis and data harmonisation. We describe the development of the Lewy Body Dementia‐Domain Rating Scale (LBD‐DRS) and a proposed roadmap for adoption and validation. Method Led by a core working group and steering committee, a three‐round Delphi survey process was used to establish consensus around the conceptual framework and preliminary content of the LBD‐DRS among invited LBD researchers and clinicians. “Consensus” was established when ≥75% of respondents concurred on any survey statement or questions. Result Consensus around the need for an LBD‐specific scale, specifically for use in early LBD, was established. After feedback was received for two early versions of LBD, a third version of LBD‐DRS has been further developed. This third version, and the results of the second Delphi survey round will be presented. A pragmatic approach, favouring an inclusive scoring approach for symptoms has been adopted, recognising that further iterations will be required once field data becomes available. Conclusion After consensus on the conceptual framework and preliminary content is established, the authors will consult with a broader range of stakeholders, including people living with LBD and their care partners, will be required to further develop LBD‐DRS. Engagement with regulatory bodies and the pharmaceutical industry will guide further development before validation studies are pursued.

Abstract BACKGROUND We sought to characterize the cognitive profile among individuals with mild cognitive impairment with Lewy bodies (MCI‐LB) to help guide future clinical criteria. METHODS Systematic review and meta‐analysis included MCI‐LB studies with cognitive data from PubMed, Embase, Web of Science, and PsycINFO (January 1990 to March 2023). MCI‐LB scores were compared to controls, MCI due to Alzheimer's disease (MCI‐AD), and dementia with Lewy bodies (DLB) groups with random‐effects models. RESULTS We included 26 studies and 2823 participants. Across all domains, the MCI‐LB group performed worse than controls and better than DLB. Compared to MCI‐AD, the MCI‐LB group performed worse in attention/processing speed ( g = –0.24, 95% confidence interval [CI]: –0.35, –0.12), attention/executive ( g = –0.42, 95% CI: –0.56, –0.28); better in verbal immediate recall ( g = 0.37; 95% CI: 0.15, 0.59) and delayed memory ( g = 0.40; 95% CI: 0.22, 0.58). DISCUSSION The cognitive profiles in MCI‐LB and MCI‐AD are consistent with established profiles in DLB and AD. Neuropsychological assessment may be helpful in differential diagnosis, even in early disease states. Highlights We performed a systematic review and meta‐analysis for cognition in mild cognitive impairment with Lewy bodies (MCI‐LB). Compared to MCI due to Alzheimer's disease (MCI‐AD), MCI‐LB had worse attention, executive function, and processing speed. Compared to MCI‐AD, MCI‐LB had better verbal immediate and delayed recall. The MCI‐LB group was worse on all cognitive domains than controls, and better than dementia with Lewy bodies. Studies used different tests and there is a need for global efforts for harmonization.

AbstractBackgroundProdromal dementia with Lewy bodies (DLB) research criteria were recently published and further work is needed to characterize the neuropsychological profile and refine clinical criteria. We performed a meta‐analysis to compare the cognitive performance of mild cognitive impairment with Lewy bodies (MCI‐LB) groups to controls, MCI due to Alzheimer’s disease (MCI‐AD), and DLB.MethodFollowing PRISMA guidelines, we searched the literature for 1) English‐language studies on MCI‐LB; 2) published January 1990‐March 2023, 3) with ≥1 standardized cognitive measure; and 4) comparison data from controls, MCI‐AD, and/or DLB. Pooled means with 95% confidence intervals were calculated for demographics. Effect sizes were calculated for group comparisons on cognitive domains. Random effects meta‐analysis models were used for group comparisons.ResultThere were 3440 participants from 27 studies across 10 countries. Mean age did not differ between groups. The percentage of female subjects was lower in the MCI‐LB group than the MCI‐AD group. Mean years of education for the MCI‐LB group was lower than the controls, but similar to MCI‐AD and DLB groups (Table 1). Compared to controls, the MCI‐LB group had lower scores for the global screening, executive function, visuospatial, language, learning, and memory domains. Compared to MCI‐AD, MCI‐LB performed better on learning and delayed recall, but similarly across other domains. Compared to DLB, MCI‐LB had better scores for global screening, executive function, language, and delayed recall (Table 2). Recognition for MCI‐LB vs. MCI‐AD; visuospatial, learning, and recognition for MCI‐LB vs. DLB could not be assessed, as fewer than 3 studies reported this data.ConclusionCognitive measures can help differentiate MCI‐LB from controls and DLB. Neuropsychological measures of learning and memory may be required to discriminate MCI‐LB from MCI‐AD in clinical practice but global screening measure scores appear insufficient in this regard. High heterogeneity across MCI‐LB studies highlights the need for harmonized neuropsychological research protocols.

AbstractBackgroundNo specific clinical rating scale currently exists for Lewy body dementia (LBD). Clinical rating scales developed for other diseases are therefore used instead for LBD clinical trials. However, these scales are not optimized for LBD and may not sufficiently reflect the complex array of LBD‐related phenomenology, making it more difficult to interpret outcome data from LBD clinical trials.MethodA working group comprised of 14 members bridging various international LBD‐focused research groups was convened to develop the first iteration of the LBD‐DRS with a focus on inclusion of key LBD related symptom domains, ensuring that any scale is mapped to regulatory expectations, and an emphasis on being patient‐centered. This draft was then subsequently presented to a broader stakeholder group (»50 participants) at the International Lewy body Dementia Conference in June 2022 for further feedback, leading to a further iteration of the scale.ResultThe LBD‐DRS has been designed to capture ratings of the frequency and severity of symptoms across the key domains relevant to LBD – cognitive, neuropsychiatric, motor, autonomic and sleep – as well as the functional impact and perceived burden of symptoms for patients and their care partners. An international Delphi exercise is now planned with many LBD‐relevant stakeholders, which will be coupled with workgroup engagement (for example, with patient‐caregiver groups) to further develop the scale with the resulting final draft anticipated for pilot use in the near future.ConclusionsIn this presentation we will elaborate on the development of the scale, key areas that it will cover as well as challenge points and next steps. Upon completion of the development and refinement of the LBD‐DRS, we propose that this scale will have utility as valid and LBD specific outcome measure in LBD clinical trials.

Abstract Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA‐binding protein 43 (TDP‐43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co‐pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co‐pathologies in DLB and their cross‐sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease‐specific and disease‐nonspecific biomarkers and how co‐pathologies can impact these biomarkers. We propose a framework for integrating multi‐modal biomarker fingerprints and step‐wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co‐pathologies.